The present invention relates to iron-salen complexes.
RNAi (RNA interference) is a phenomenon in which double-stranded RNA (dsRNA) is taken up into various organisms or cells, resulting in the destruction of complementary mRNA. Long (generally 200 base pair or more) dsRNA is cut up into shorter 21 to 25 base pair siRNA (short interfering RNA) by Dicer, a type of ribonuclease in cells. The double-stranded siRNA is unwound into single strands by helicase in the cytoplasm, resulting in the formation of RISC (RNA-induced silencing complexes) primarily by antisense strands and some proteins. The interaction between the siRNA antisense strands and mRNA results in binding to complementary transcripts, and the ribonuclease activity of the RISC thereby results in the destruction of mRNA and thus gene silencing (the suppression of gene expression).
Because long dsRNA cannot be introduced without modification into mammalian cells, 21 bp chemically synthesized double-stranded siRNA is used. Synthetic double-stranded siRNA has been exploited for gene functional analysis and the screening of target genes because there is no need for the preparations and time required to prepare knock out mice with homologous recombinants, and knock down can be readily brought about by the targeted mRNA degradation using cultured cells or animal models.
The above compounds would be administered to the living body to reach the affected site and bring about pharmacological effects in the local affected site, leading to therapeutic efficacy, but without reaching and treating unaffected tissue (that is, normal tissue). How to effectively guide the drug to the affected site is thus critical in terms of treatment strategy. Techniques for thus guiding the drug to the affected site are referred to as drug delivery, and have become the subject of much recent research and development. This drug delivery has at least two advantages. One is that a sufficiently high concentration of the drug is obtained in the affected tissue. Pharmacological effects will not show up unless the drug concentration is at a certain level in the affected area, and no therapeutic effects can be anticipated at lower concentrations. The second is that the drug is guided only to the affected tissue and not unnecessarily to normal tissue. This can suppress adverse drug reactions.
The most effective drug delivery of this type is cancer treatment with anti-tumor agents. As most anti-tumor agents inhibit the growth of cancer cells that activate mitosis, they also end up inhibiting cell growth in normal mitosis-activating tissue, such as bone marrow, hair roots, and gastrointestinal mucosa. Patients given anti-tumor agents thus suffer from adverse drug reactions such as anemia, hair loss, and vomiting. As such adverse drug reactions impose a major burden on patients, a problem is that doses must be limited, preventing the pharmacological effects of the anti-tumor agents from being fully exploited. Additionally, in the worst cases, patients are at risk of dying from the adverse drug reactions. There is thus a need to be able to achieve effective therapy while suppressing adverse drug reactions by guiding anti-tumor agents to cancer cells by means of drug delivery to allow the agents to be concentrated in cancer tissues and bring about the intended pharmacological effects.
Applications to the treatment of erectile dysfunction, for example, may also be contemplated in addition to anti-tumor agents. There are cases in which drugs for the treatment of erectile dysfunction have interacted with nitrates, leading to serious systemic hypotension and death, a problem which occurs particularly in middle-aged or older men with heart disease. That is because drugs for the treatment of erectile dysfunction are not necessarily limited to the affected area, and affect the systemic vasculature, increasing the vasodilating action of nitrates. Drug delivery may therefore also allow drugs for the treatment of erectile dysfunction to be guided to and concentrated in the affected area to bring about the intended pharmacological effect, thereby suppressing adverse drug reactions resulting from interactions with nitrates.
Delivery to affected tissue using carriers has been studied as a specific method of drug delivery, but this involves loading the drug on a carrier that is readily concentrated in the affected area to transport the drug on the carrier to the affected area. The use of various types of antibodies, microspheres, or magnetic substances as carriers has been studied. Out of these, magnetic substances have been considered useful, and methods for allowing a carrier which is a magnetic substance to adhere to drugs to allow the drug to be concentrated in the affected area by a magnetic field have been studied (such as Japanese Laid-Open Patent Application No. 2001-10978). This method is considered an especially effective method for highly cytotoxic anti-tumor agents because the delivery method is convenient and affected areas can be targeted.
However, it is difficult to make practical use of magnetic substances as carriers in the manner described above because, as noted previously, they are difficult to administer orally, the carrier molecules are generally extremely large, and technical problems have been pointed out with the binding strength to, and affinity for, drug molecules.